An efficient synthesis of dialkyl phosphorocyanidates

Article abstract of DOI:10.1080/104265090917673

Dialkyl phosphorocyanidates 2a-2g were prepared in high yield from dialkyl phosphorochloridates and hydrogen cyanide in the presence of triethylamine in ether. The white precipitates formed in the reaction of diethyl phosphorochlorodates and triethylamine were verified as triethylammonium chloride, not the similar phosphoryltriethylammonium chloride by FAB-MS, ESI-MS, ³¹P-NMR, and ¹H-NMR. Copyright Taylor & Francis Inc.

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Phosphorus, Sulfur, and Silicon
and the Related Elements
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An Efficient Synthesis of Dialkyl
Phosphorocyanidates
Daoming Sun a , Enxue Shi a , Junhua Xiao a &
Chengxin Pei a
a Beijing Institute of Pharmaceutical Chemistry,
Beijing, P.R. China
Published online: 19 Aug 2006.
To cite this article: Daoming Sun , Enxue Shi , Junhua Xiao & Chengxin Pei (2005) An
Efficient Synthesis of Dialkyl Phosphorocyanidates, Phosphorus, Sulfur, and Silicon and
the Related Elements, 180:9, 2155-2161, DOI: 10.1080/104265090917673
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Phosphorus, Sulfur, and Silicon, 180:2155–2161, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090917673
An Efficient Synthesis of Dialkyl Phosphorocyanidates
Daoming Sun
Enxue Shi
Junhua Xiao
Chengxin Pei
Beijing Institute of Pharmaceutical Chemistry, Beijing, P.R. China
Dialkyl phosphorocyanidates 2a–2g were prepared in high yield from dialkyl phos-
phorochloridates and hydrogen cyanide in the presence of triethylamine in ether.
The white precipitates formed in the reaction of diethyl phosphorochlorodates and
triethylamine were verified as triethylammonium chloride, not the similar phos-
31
1
phoryltriethylammonium chloride by FAB-MS, ESI-MS, P-NMR, and H-NMR.
Keywords Cyanation; phosphorochloridates; phosphorocyanidates; phosphoryltriethyl-
ammonium chloride
As a kind of important reagent in organic synthesis, diethyl phospho-
rocyanidate (DEPC) has been used widely to prepare amides, thiol
esters, thiocyanates, a-aminonitriles, cyanophosphates, nitriles, a, β-
unsaturated nitriles, and so on.1
Except for the conventional Arbuzov method,2 we have recently
developed two new methods in synthesis of phosphorocyanidates
from phosphorochloridates.3,4 Since it was reported that phosphono-
cyanidates can be obtained from the cyanation of phosphonochloridates
by hydrogen cyanide,5 we then examined the possibility of prepara-
tion of phosphorocyanidates in a similar way and received satisfactory
results.
RESULTS AND DISCUSSION
Reaction of diethyl phosphorochloridate (DEPCl) with hydrogen
cyanide in different solvents was studied detailedly (Table I). In con-
trast to the two-phase reaction of DEPCl with potassium cyanide,3 the
Received February 11, 2004; accepted November 7, 2004.
Address correspondence to Daoming Sun, Beijing Institute of Pharmaceutical Chem-
istry, Beijing, 102205, P.R. China. E-mail: sundm7114@163.com
2155

2156
D. Sun et al.
TABLE I Reaction Between DEPCl
and HCN in Different Solvents
a
Entry
Solvent
ET(30)
Yield (DEPC, %)
1
2
3
4
5
6
C6H6
Et2O
THF
CH2Cl2
DMF
34.5
34.6
37.4
41.1
43.8
46.6
40
94
54
73
22
42
CH3CN
aGC yield %.
polarities (ET (30)) of solvents showed no obvious effect on the homoge-
neous cyanation of DEPCl by hydrogen cyanide. However, there were
more byproducts in the solvents containing an unsaturated bond such
as DMF and methyl nitrile. Moreover, more anhydrides were generated
with difficultly drying solvents, for example, THF and CH2Cl2. In ether,
the yield of phosphorocyanidates was 94%. Thus, we employed ether as
reaction solvent.
The complete cyanation of DEPCl by hydrogen cyanide in ether ge-
nearally took only 15 min and reaction temperature nearly had ef-
fects on cyanation. Considered convenient treatment, temperature of
cyanation was kept 10–20◦. Dialkyl phosphorocyanidates 2a–2g were
prepared in high yield (85–95%) from dialkyl phosphorochloridates
1a–1g and hydrogen cyanide in presence of triethylamine in ether
(Scheme 1).
SCHEME 1
It was found that the reaction mixture immediately became turbid
and white precipitates appeared when triethylamine was added into
DEPCl in ether. Moreover, it should be noted that DEPCl, without Et3N,
did not react with HCN. So Et3N must play a key role in this cyanation
and white precipitates may be possiblely powerful intermediate.
Hirschman argued6 that phosphonochloridates could react with tri-
ethylamine to give phosphonyltriethylammonium chloride 3, which
were highly reactive phosphonylating agents, superior to phospho-
nochloridates, affording a higher yield of phosphonate esters and

Synthesis of Dialkyl Phosphorocyanidates
2157
SCHEME 2
amides. Thus, the white solids would probably be novel diethyl phos-
phonyltriethylammonium chloride 4a served as the intermediates in
the above rapid cyanotion process (Scheme 2).
As for intermediate 4a, we tested its probability by a fast atom bomb
mass (FAB-MS) and electrospray ionization mass (ESI-MS). The FAB-
MS and ESI-MS spectrums of the isolated white precipitates are shown
in Figures 1 and 2.
It was unexpected, however, that characteristic position m/z 236 of
the positive ion of the proposed intermediate 4a was not detected by
FAB-MS and ESI-MS as shown in Figures 1 and 2. On the contrary,
the peak m/z 239, accompanied by a distinct chloride isotope, should be
responsible for the fragment ion (Et3N)2H+Cl. So the white solids may
not be the predicted intermediates 4a.
To verify our suspicion, the isolated white precipitates were added to
ether and reacted with hydrogen cyanide. If cyanation proceeded via the
intermediate 4a, the corresponding phosphonates must be generated
after cyanation. However, the result monitored by GC showed that there
FIGURE 1 Positive ion FAB-MS spectrum of the white precipitates.

2158
D. Sun et al.
FIGURE 2 Positive ion ESI-MS spectrum of the white precipitates.
was nothing besides ether and triethylamine, which meant that the
isolated white precipitates did not contain phosphorus ingredient.
In order to confirm our experimental result, further evidence for the
1
structure of white solids came from the studies of 31P-NMR and H-
NMR. Nothing was observed in the 31P-NMR spectrum and the study
1
of the H-NMR showed that the white solids contained only Et3N and
a few ether (Figure 3). That is, the white solids were not the predicted
phosphonyltriethylammonium salts, but the triethylammonium salts.
FIGURE 3 1H-NMR spectrum of the white precipitates.

Synthesis of Dialkyl Phosphorocyanidates
2159
FIGURE 4 (a) 31P-NMR spectrum of DEPCl. (b) 31P-NMR spectrum of the
filtrate filtrated out of the triethylammonium salts.
Since the white solids were not intermediates 4a, whether the
structure of phosphorochloridates had changed or not? As shown by
Figure 4, the 31P-NMR chemical shifts of the starting material DE-
PCl was 43.915 ppm, which was the same as the chemical shift of
the filtrate (43.745 ppm), which was filtrated out of the triethylam-
monium salts. More important, no novel phosphorous compounds, un-
like Hirschmann’s studies, appeared by treatment DEPCl with triethy-
lamine besides a few anhydrides (26.183 ppm). So we held that the
structure of DEPCl kept unchanged after triethylamine added.
After all attempts to investigate the possibility of phosphoryltriethy-
lammonium salts 4a failed, we considered the role of triethylamine in

2160
D. Sun et al.
this reaction. In many conventional phosphonate synthesis, triethy-
lamine is added along with nucleophile as an acid scavenger. We in-
vestigated other typically organic base’s effects on cyanation such as
tributylamine and pyridine. However, no evidence for reaction of DE-
PCl and HCN was seen in the presence of tributylamine or pyridine. So
the triethylamine acts as not only acid scavenger, but also as a catalyzer
in this cyanation. Though the structure of DEPCl, in the presence of
triethylamine, did not change, the reactivity of P Cl bond had been
enhanced by triethylamine, which was an impetus to the formation of
phosphorocyanidates. The reason why tributylamine or pyridine could
not catalyze this reaction might due to a steric effect. In addition, a few
triethylammonium salts formed in the reaction of DEPCl and triethy-
lammine might be a little water in the reaction system in result of the
uncompleted drying.
Compared with Hirschman’s experiment, otherwise, we cannot deny
the viewpoint about intermediate resulting from different starting ma-
terial and reactive conditions. Many assignments on the reaction mech-
anism need to be made.
In summary, we have given another efficient preparation of dialkyl
phosphorocyanidates. The white precipitates, which were generated by
diethyl phosphorochlorodates and triethylamide, were verified as tri-
ethylammonium salts, not the similar phosphoryltriethylammonium
salts.
EXPERIMENTAL (CAUTION: ALL PROCEDURES MUST BE
CARRIED OUT IN GOOD FUME CUPBOARDS)
GC was recorded on a Varian CP-3800 spectrometer, into IR, on a Bio-
Rad FTS185 spectrometer, 31P-NMR on a Varian UNITY500 spectrom-
eter using 85% H3PO4 as external reference, MS on a Finnigan Mat
TSQ70 spectrometer, and elemental anal. on Flash EA 1112 series.
General procedure for dialky phosphorocyanidates 2a–2g:
To the mixture of dialky phosphorochloridate (5 mmole) and triethy-
lamine (5 mmole) in ether (2 mL) was added the solution of hydrogen
cyanide (6 mmol) in 0.5 mL ether at 10–20◦. After stirring for 15 min,
the mixture was filtrated, the filtrate was concentrated in vacuo, and
distillation gave the product.
Diethyl Phosphorocyanidate 2a
Yield 94%; bp 52∼54 (0.6 mm); IR 2206.5 (υC≡N); 31P-NMR (CDCl3)
−20.5; MS 164 (M+1); elemental anal.: Cacl. C, 36.82; H, 6.18; N, 8.59;
Found: C, 36.76; H, 6.24; N, 8.75.

Synthesis of Dialkyl Phosphorocyanidates
2161
Dipropyl Phosphorocyanidate 2b
Yield 95%; bp 62∼64 (0.4 mm); IR 2208.2 (υC≡N); 31P-NMR(CDCl3)
−19.6; MS 192 (M+1); Elemental Anal.: Cacl. C, 43.98; H, 7.38; N, 7.33;
Found: C, 43.88; H, 7.44; N, 7.37.
Diisopropyl Phosphorocyanidate 2c
Yield 88%; bp 53–55 (0.2 mm); IR 2208.4 (υC≡N); 31P-NMR (CDCl3)
−23.1; MS 192 (M+1); Elemental Anal.: Cacl. C, 43.98; H, 7.38; N, 7.33;
Found: C, 44.12; H, 7.28; N, 7.41.
Dibutyl Phosphorocyanidate 2d
Yield 90%; bp 70∼71 (0.2 mm); IR 2208.8 (υC≡N); 31P-NMR (CDCl3)
−20.1; MS 220 (M+1); Elemental Anal.: Cacl. C, 49.31; H, 8.28; N, 6.39;
Found: C, 49.38; H, 8.33; N, 6.45.
Diisobutyl Phosphorocyanidate 2e
Yield 92%; bp 69–71 (0.1 mm); IR 2208.9 (υC≡N); 31P-NMR (CDCl3)
−19.5; MS 220 (M+1); Elemental Anal.: Cacl. C, 49.31; H, 8.28; N, 6.39;
Found: C, 49.25; H, 8.24; N, 6.54.
Disecbutyl Phosphorocyanidate 2f
Yield 85%; bp 70∼71 (0.2 mm); IR 2208.5 (υC≡N), 31P-NMR (CDCl3)
−22.1; MS 220 (M+1); Elemental Anal.: Cacl. C, 49.31; H, 8.28; N, 6.39;
Found: C, 49.35; H, 8.17; N, 6.42.
Dianyl Phosphorocyanidate 2g
Yield 87%; bp 102∼104 (0.5 mm); IR 2208.7 (υC≡N); 31P-NMR (CDCl3)
−19.9; MS 248 (M+1); Elemental Anal.: Cacl. C, 53.43; H, 8.97; N, 5.66;
Found: C, 53.47; H, 8.94; N, 5.61.
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